CD36 is a membrane scavenger receptor that recognizes several ligands including native and oxidized lipoproteins and long chain fatty acids. Research supported by this grant has resulted in the identification of CD36 as an important facilitator of long-chain fatty acid uptake by key metabolic tissues. In the last funding period we studied animal models with genetically altered CD36 levels to examine the molecular mechanims that mediate the interaction between the metabolisms of fatty acids and glucose and how this impacts susceptibility to insulin resistance. We explored the role of CD36 in cross adipose tissue where we showed that it influences PPARgamma activation and the secretion of leptin and adiponectin. Finally we documented the role of fatty acids and the transcription factor FoxO1 in regulation of CD36 membrane localization and function in muscle cells. This application follows up on our recent findings that complex processing of CD36 via palmitoylation and ubiquitination of residues in its carboxyl domain mediates its acute regulation by ligands (fatty acids and oxidized lipoproteins) or regulators (insulin and FoxO1). Our hypothesis is that this regulated processing influences sorting of the protein to the membrane and its cellular redistribution. We propose that ubiquitination of CD36 by its ligands fatty acids and OxLDL is a protective mechanism that limits excess uptake of these lipids via inducing CD36 degradation and dysfunction of this mechanism would lead to pathology. We propose to examine the mechanisms involved in regulation of CD36 processing and the implications with respect to fatty acid metabolism and insulin resistance. We will also explore how intracellular trafficking of CD36 influences lipid storage at the level of biogenesis and maturation of lipid droplet in adipocytes. We will test the hypothesis that adipose tissue CD36 exerts a protective effect with respect to pathophysiology due to positive energy balance by promoting activation of adipose PPARgamma and lipid storage which minimizes ectopic fat accumulation. The work proposed has potential clinical significance. In humans, polymorphisms in the CD36 gene are common and CD36 variants have been linked to dylipidemia, susceptibility to the metabolic syndrome and to cardiovascular disease. A better understanding of the molecular regulators of CD36 function in FA uptake and processing will help in designing better therapies that prevent or reverse dysfunctional FA metabolism and its deleterious consequences. PUBLIC HEALTH RELEVANCE: The membrane protein CD36 facilitates long chain fatty acid uptake by key metabolic tissues, e.g. muscle, adipose tissue, heart and intestine. Our recent data indicate that fatty acids acutely enhance CD36 turnover via its ubiquitination, which targets it to degradation. We propose that dysfunction of this protective mechanism would lead to pathology as a result of excess fatty acid uptake. The work proposed will explore the mechanisms regulating CD36 turnover and their implications with respect to insulin resistance. The work has potential clinical significance. In humans, abnormalities in fatty acid metabolism correlate with abnormal CD36 levels at the membrane. In addition common variants in the CD36 gene have been linked to dylipidemia, susceptibility to the metabolic syndrome and to cardiovascular disease.